Clopidogrel bisulfate corresponds to the empirical formula C16H16ClNO2S.H2SO4. Chemically it is methyl (+)-(S)-alpha-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1), having the following structural formula.

Clopidogrel is an inhibitor of platelet aggregation and is marketed as an antianginal agent, antiplatelet agent and is found to decrease morbid events in people with established atherosclerotic cardiovascular disease and cerebrovascular diseases.
The therapeutic application of Clopidogrel as blood-platelet aggregation inhibiting agents and antithrombotic agent and its preparation is disclosed in U.S. Pat. No. 4,529,596.
U.S. Pat. No. 4,847,265 describes the process for the preparation of the hydrogen sulfate salt of Clopidogrel.
Various other strategies to prepare Clopidogrel are disclosed in WO 98/51681, WO 98/51682, WO 98/51689, WO 99/18110, U.S. Pat. No. 5,036,156, U.S. Pat. No. 5,132,435, U.S. Pat. No. 5,139,170, U.S. Pat. No. 5,204,469 and U.S. Pat. No. 6,080,875.
U.S. Pat. No. 4,847,265 discloses that the dextrorotatory enantiomer of formula (I) of Clopidogrel has an excellent antiaggregant platelet activity, whereas the corresponding levorotatory enantiomer is less tolerated and is less active. U.S. Pat. No. 4,847,265 relates to the dextrorotatory enantiomer and its pharmaceutically acceptable salts with platelet aggregation inhibiting activity.
Subsequently filed Patent Application WO 99/65915 (U.S. Pat. No. 6,429,210) titled “Polymorphic Clopidogrel hydrogen sulfate form”, which is herein incorporated by reference, discloses the existence of a specific polymorphic Form II of the hydrogen sulfate of (S)-(+)-Clopidogrel (m.p.=176±3° C.). It is also disclosed in this patent application that the earlier processes described in the U.S. Pat. No. 4,847,265 gives Form I (m.p. 184±3° C.). These two crystalline polymorphic forms I and II differed in their stability, physical properties, spectral characteristics and their method of preparation. However, both the polymorphs have similar bioavailability, as shown in their bioequivalence in healthy human volunteers.
Although, U.S. Pat. No. 4,847,265 reports the formation of (S)-(+)-Clopidogrel bisulfate salt with m.p. 184° C., it was disclosed as Form I only in patent application WO 99/65915. However, a reproducible and consistent method for the preparation of Form I with chirally pure material (ee>99%) was in doubt since chiral purity of the material (Clopidogrel bisulfate) with m.p. 184±3° C., disclosed in U.S. Pat. No. 4,847,265 was not precisely known.
In fact, we have observed that formation of Form I of (S)-(+)-Clopidogrel bisulfate with chiral purity>99% e.e. is inconsistent and difficult to reproduce using the procedures reported in U.S. Pat. No. 4,847,265 and WO 99/65915 whereas the formation of Form II is extremely facile and consistent with optically pure (S)-(+)-Clopidogrel free base.
We have earlier disclosed improved processes for the manufacture of (S)-(+)-Clopidogrel bisulfate & its intermediates [Indian Patent Applications 84/MUM/2001 (WO 02059128/U.S. Pat. No. 6,635,763), & 335/MUM/2001] which are cited herein in their entirety as reference.
We have also disclosed hydrated form of amorphous Clopidogrel bisulfate as well as methanolates, ethanolates and containing different form stabilizers [Indian patent application 1154/MUM/2003 and 413/MUM/2003], which are also incorporated as reference.
Amorphous Clopidogrel bisulfate and other solvated forms (1-butanol, 2-butanol, isopropanol, 1-propanol) as well mixtures of amorphous form with Form I and Form II and processes for preparing them have been disclosed in Teva's application no. WO 03/051362 A2, which is cited herein as reference. However, this application does not disclose amorphous Clopidogrel bisulfate hydrate.
Teva's application also discloses processes for preparing Form I and Form II of Clopidogrel bisulfate. The Form I is prepared by contacting the amorphous form disclosed therein in ethers preferably diethyl ether or MTBE. These processes have the following disadvantages:    i. diethyl ether and MTBE are very volatile and inflammable hence are hazardous to work with;    ii. the process is difficult to be scaled up to plant scale;    iii. problem of recovery of antisolvents further making the process economically unfeasible.
We herein disclose improved processes for preparing amorphous Clopidogrel bisulfate, amorphous Clopidogrel bisulfate hydrate, amorphous Clopidogrel bisulfate solvates, with high optical purity (ee>99%).
We also disclose improved processes for preparing Form I and Form II of Clopidogrel bisulfate. Also disclosed are amorphous Clopidogrel bisulfate, Form I and Form II of Clopidogrel bisulfate with characteristic impurity profile.